Role of pro-inflammatory and homeostatic chemokines in diabetic nephropathy

Summary and hypothesis Role of pro-inflammatory chemokines in
diabetic nephropathy Beyond hemodynamic and metabolic abnormalities
associated with diabetes, the role of inflammation in development
and progression of diabetic nephropathy is well accepted.
Recruitment and activation of macrophages in different renal
compartment is considered to be hallmark of all inflammation in
diabetic nephropathy. Although recruitment of macrophages to the
renal compartment has been extensively studied, the exact
mechanisms involved are still to be explored. The
chemokine-chemokine receptor interactions are implicated to be
mainly responsible for trafficking and infiltration of different
monocytes and macrophages. Contribution of macrophages to the
development of DN can be addressed in either by inhibiting
chemokines or chemokine receptor associated with diabetes. We
hypothesized that inhibition of CCL2 may inhibit macrophages
infiltrating into different compartments in kidney and inhibition
started at earlier stage of disease progression may show more
beneficial effects than CCL2 blockade at late stage of DN. To
address the involvement of additional chemokine receptors we
hypothesized that blocking CCR5 and CCR2 simultaneously might have
some additive or synergistic effects. Role of homeostatic
chemokines in diabetic nephropathy Homeostatic chemokies are mainly
involved in hematopoeisis, immune cell survival and adaptive immune
responses. CXCL12 attracted our attention as it is being
extensively studied and reported to be responsible for different
functions like stem cell survival and homing and trafficking to
different compartments. The role of CXCL12 in diabetic nephropathy
has not been explored yet. CXCL12 is constitutively expressed by
different renal cells. It may contribute to tissue repair and
inhibit disease progression by stem cell recruitment or may cause
increased tissue fibrosis and aggravate the disease. We
hypothesized that CXCL12 plays role in development and progression
of diabetic nephropathy. In order to address this question we used
CXCL12 blocker in a mouse model of diabetic nephropathy.